NO171063B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACCEPTABLE, ALCOXY-SUBSTITUTED DIHYDROBENZOPYRANE-2 CARBOXYLATE DERIVATIVES - Google Patents

Description

The present invention relates to an analogous process for the production of therapeutically active, alkoxy-substituted dihydrobenzopyran-2-carboxylate derivatives. These derivatives act as leukotriene B4 (LTB4) antagonists.

Previously, compounds with structures similar to formula I have been described, with the exception that in the earlier compounds, R<2> in formula I is replaced by hydrogen. For example:

Journal of Medicinal Chemistry, 1977, 20, (3) 376 broadly describes the compounds where R<2> from formula I is hydrogen.

EPA 79,637 generically describes a formula comprising the compounds of formula I wherein -OR<2> is -O-alkyl and B is C=0, but does not exemplify or otherwise enable the preparation and use of such compounds. EPA 79,637 describes the intermediates for the preparation of the compounds prepared according to the present invention, where -OR<2> in formula I is -OH. EPA 79,637 does not demonstrate the selective LTB4 antagonist activity of the compounds prepared according to this invention.

US 4,281,008, US 3,822,148 and US 4,006,245 generically describe formulas comprising the compounds of formula I wherein -OR<2 >is -O-alkyl or O-Me and B is C=0 but do not exemplify or enable otherwise the preparation and use of such compounds, and also does not describe the selective LTB4 antagonist activity of the compounds prepared according to the present invention.

The Journal of Medicinal Chemistry, 1977, vol. 20 (3): 376 describes a compound similar to the compounds of formula I except that the acyl and alkyl substituents adjacent to -OR 2 in formula I are not present. The Journal of Medicinal Chemistry article also describes a compound similar to the compounds of formula I with the exception of a hydroxy substituent on the -0-(CH2)x-0- linking group.

Prior art generally describes the above compounds as LTD4 antagonists for use as anti-allergy compounds or as antagonists of SRS-A, the slow-reacting agent of anaphylaxis. In sharp contrast to this, the compounds of formula I are selective LTB4 antagonists which are useful in the treatment of inflammatory diseases.

Leukotriene D4 and C4 (LTD4/LTC4) and leukotriene B4 (LTB4) are products of the arachidonic acid metabolic pathway. LTD4 and LTC4 are associated with smooth muscle contraction and constrict guinea pig small intestine, human and guinea pig trachea, and human guinea pig pulmonary artery and vein. LTB4 is associated with neutrophil stimulation and is characterized by chemotaxis, aggregation and degranulation. LTB4 is considered to be an important mediator of inflammation. High levels of LTB4 have been detected in arthritis, gout, psoriasis and inflammatory bowel disease. Antagonists of LTB4 are thus useful in the therapy of such diseases.

Gastroenterology, 1985: 88: 580-7 discusses the role of arachidonic acid metabolites in inflammatory bowel disease.

British Medical Bulletin, (1983), vol. 39, No. 3, pp. 249-254, generally discusses the pharmacology and pathophysiology of leukotriene B4.

Biochemical and Biophysical Research Communications, Vol. 138, No. 2 (1986), pp. 540-546, discusses the pharmacology of a specific LTB4 antagonist having a different structure than the compounds of this invention.

The present invention therefore relates to an analogous method for the production of therapeutically active, alkoxy-substituted dihydrobenzopyran-2-carboxylate derivatives with the formula:

and pharmaceutically acceptable salts thereof

in which R<1> stands for alkyl with 2-6 carbon atoms, alkenyl with 2 to 6 carbon atoms or CH2R in which R stands for cyclopropyl; R<2> stands for methyl or ethyl; R<3> stands for alkyl of 1 to 5 carbon atoms; W stands for (CH 2 ) X where x is 2 to 5, alkenyl of 3 to 5 carbon atoms, alkynyl of 3 to 5 carbon atoms, or cyclopentyl; R<4> stands for hydrogen, alkyl of 2 to 5 carbon atoms; B stands for CE2, C=0 or CH-OH; R<5> stands for hydrogen, alkyl with 1 to 4 carbon atoms, or R<5> and R<*> > together optionally stand for a carbon to carbon bond; and A represents -Z-C02R<7> or -Z-CONR9R10 where R<7> represents hydrogen or alkyl of 1 to 4 carbon atoms, R<9> and R<10 >represent hydrogen, alkyl of 1 to 4 carbon atoms, and in which Z is a direct bond or an ethylene chain, characterized by alkylating a compound of the general formula:

wherein R<1>, R<3>, R<4>, R<5>, W, Å and B have the same meanings as described above and, if desired, hydrolyze group A to provide the free acid which is optionally converted -formed into the pharmaceutically acceptable salt.

These compounds are selective antagonists of leukotriene B4 (LTB4) with little or no antagonism to leukotriene D4 (LTD4) and are useful as anti-inflammatory agents for the treatment of inflammatory bowel disease, arthritis, gout and psoriasis.

Pharmaceutically acceptable salts such as ammonia, sodium, potassium, alkaline earth, tetraalkylammonia, etc. is included in the invention.

The compounds prepared according to this invention are generally prepared by alkylating the previous phenolic hydroxy (R<2>=H) compounds to form compounds of formula I by conventional techniques. The reaction of phenol hydroxy (R<2>=H) with methyl iodide in potassium carbonate provides ether. Dimethylsulphate in acetone and base is also useful for the preparation of ethers. Alternative intermediates can be alkylated prior to the formation of the -O-(CH2)-O bridge. Hydrolysis of ester compounds in the presence of lithium hydroxide and methanol provides the acid compounds.

The biological activity of the compounds produced according to the present invention is indicated by the following tests.

Preparation of human neutrophils

Neutrophils were purified from venous blood of normal donors using standard techniques of dextran sedimentation, centrifugation on Ficoll-paque (Pharmacia) or Histopaque sterile solution (Sigma) and hypotonic lysis (breakdown of red blood cells) (Boyum, A., Isolation of Leukocytes From Human Blood: Further Observations. Scand. J. Lab. Clin. Invest., 21 (Suppl. 97): 31, 1968). The purity of isolated neutorphiles was >95#.

LTBfl receptor binding assay

Neutrophils (4 - 6 x 10<6>) in 1 ml Hanks' balanced salt solution containing 10 µM HEPES buffer (HBSS), pH 7.4 and 30 µM nordihydroguaiaretinoic acid were incubated with 0.6 x 10~<9> M (<3>H) LTB4 in the presence or absence of the test compounds. Incubation was performed at 0°C for 45 minutes and terminated by addition of 5 ml of ice-cold HBSS followed by rapid filtration of incubation mixture under vacuum through GF/C glass fiber filters. The filters were further washed with 10 ml of HBSS and the radioactivity was determined. Specific binding was defined as the difference between total binding and nonspecific binding that was not displaced by 10~<7>M unlabeled LTB4. All data refer to specific binding.

Human neutrophil degranulation assay

Neutrophil degranulation was determined by measuring the release of myeloperoxidase activity into the incubation medium. Neutrophils (3 x 10<6>) in 1 ml HBSS solution were preincubated with cytochalasin B (5 µg) at 37°C for 5 minutes, followed by preincubation with the test compounds for 7 minutes. Neutrophils were then incubated for 2 to 20 min with either LTB4 (5 x 10-<8>M) or the chemotactic peptide f-met-leu-phe- (5 x 10~<6>M) to induce degranulation. After incubation, the samples were centrifuged and myeloperoxidase was extracted from the cell pellets by sonication in phosphate buffer containing 0.4% Triton X-100. Triton X-100 was also added to the supernatants to a concentration of 0.456. The supernatants and pellet extracts were then analyzed spectrophotometrically for myeloperoxidase activity by determining the rate of degradation of H2O2 with o-dianisidine as hydrogen donor as described by Renlund et al., (Renlund, D.G., MacFarlane, J.L., Christensen, R.D., Lynch, R.E., and Rothstein, G., A Quantitative And Sensitive Method For Measurement Of Myeloperoxidase, Clinical Research 28:75A, 1980). Myeloperoxidase activity released into the supernatant was expressed as a percentage of the average total activity (pellet plus supernatant).

Guinea pig LTB4-induced skin chemotaxis

(Attraction or repulsion of a chemical nature)

The test compound was administered intravenously or intragastrically (into the stomach) at various times before injection of leukotriene B4 (LTB4). LTB4 was diluted in phosphate buffered saline (PBS) and 35 ng in 0.2 ml was injected into the skin of shaved backs of anesthetized guinea pigs. PBS was injected as a control. Four hours later, the animals were sacrificed, the skin was removed and stored frozen (-70°C). The injection sites were removed with a skin punch and mechanically homogenized (Polytron, Brinkmann Instruments). Myeloperoxidase (MPO), a marker enzyme for neutrophils were extracted with 0.5# hexadecyltrimethylammonium bromide in 50 mM potassium phosphate buffer (pH 6.0), using sonication and the freeze-drying methods. After centrifugation (40,000 x g, 30 minutes), the enzyme activities in the supernatants were analyzed spectrophotometrically (A46q) by measuring the breakdown of hydrogen peroxide by o-dianisidine after 15 minutes. MPO activity was found to be proportional to the number of neutrophils. In guinea pigs, the level of MPO activity increased with the amount of LTB4 injected.

Modified Bovden chamber- k. iemotaxis

Human neutrophils were isolated from citrated peripheral blood using standard dextran sedimentation techniques, followed by centrifugation on Histopaque sterile solution (Sigma) or Ficoll-paque (Pharmacia) and hypotonic lysis (breakdown of red blood cells). A final cell suspension of 3.4 x 10<6> neutrophils/ml of HEPES-buffered Hank's Balanced Salt Solution (HBSS, pH 7.3) was added to the upper well (0.8 ml) of a modified Boyden chamber (blind well). The lower well (0.2 ml), separated by a polycarbonate membrane Nukleopore Corp.), contained HBSS or 3 x 10"<8>M LTB4 in the presence or absence of test compound. After 90 minutes of incubation at 37"C for 5 % C02-95# air, the cells from the lower well were lysed and nuclei were counted in a Model S-Plus-IV Coulter Counter. Percent inhibition was calculated from the cell counts corrected for random migration by subtracting the mean of the HBSS control.

The compounds prepared in the present invention can be administered in a large number of dosage forms. The preferred method of delivery will be oral and in such a way as to establish the effect of the inhibitor. In inflammatory conditions such as arthritis, the compounds can be injected directly into the affected joint. The compounds can also be administered in oral dosage forms such as tablets, coffee, pills, powders or grains. They can be introduced intraperitoneally, subcutaneously or intramuscularly using known pharmaceutical methods. Topical application of balms and ointments is useful for treating psoriasis. Regardless of which mode of administration is chosen, the compounds are formulated into pharmaceutically acceptable dosage forms by conventional known pharmaceutical methods.

LTD4 antagonism 1 marsupial intestine

Fresh segments of guinea pig intestine were suspended in 2 ml tissue bath containing oxygenated modified Tyrode solution. After an equilibration period, an agonist dose-response curve was generated by exposing each tissue to four different LTD4 doses and then measuring the subsequent contractile heights. The intestinal segments were washed and rested between agonist exposures. After this, the tissue was incubated with a single concentration of test compound and the agonist dose-response pattern was repeated. The dosage is a measure of the antagonist's ability to shift the agonist dose-response curve to the right. It appears as the concentration of agonist necessary to achieve a given level of response in the presence of (A') versus the absence of (A) of antagonist. For example, if the test concentration of the compound had no effect on agonist-induced response (A'=A) the dose ratio would be approximately 1. Dose ratios increase if the compound inhibits agonist-induced response. A dose ratio value is determined for each strip of intestine used to test the antagonist. If the dose ratios increase as a function of increasing antagonist concentration, these data can be calculated by Schild analysis to determine whether the inhibition is competitive and, if so, the pÅ 2 value of the compound. Schild analyzes examine the linearity of the function described by the dose relationships written as log (A'/A) versus antagonist concentration. If linearity is confirmed and the slope number approaches -1, the inhibition is considered to be competitive. pA2 is the negative log of the antagonist concentration required to produce a dose ratio of 2. This value is considered to be a measure of the affinity of the competitive antagonist.

Leukotriene D4 receptor analysis using guinea pig lung preparations

The following description describes an LTD4 radioreceptor assay that is used to identify compounds that inhibit LTD4 binding to lung membrane preparations. Membrane preparations: For each membrane preparation, 10-11 male Hartley guinea pigs, weighing less than 350 g, were sacrificed by guillotine. The lungs were quickly removed and placed in ice-cold 50 mM Trisma 7.0 buffer. After all the lungs were collected, they were all examined to see if they were free of bronchial tissue, at least to the tertiary branching level as observed through a dissecting lamp. The tissue was cut with a razor blade on a moistened paper towel and placed into fresh ice-cold Trisma 7.0 buffer. When all the tissues had been thus treated, they were pooled, and the liquid was drained and then weighed. Nine volumes of cold buffer were added, and the tissue was polytroned in 6-10 second bursts with a 1 minute cooling period in an ice bath between each burst. The homogenate was filtered through gauze and centrifuged at 1085 x g for 15 minutes at 4°C. The supernatants were saved and centrifuged at 40,000 x g for 20 min at 4°C. This time the supernatants were discarded and the pellets were resuspended in 30-35 ml of fresh Trisma 7.0 buffer with 1-10 second bursts with a polytron. The substances were again centrifuged at 40,000 x g. The supernatants were again discarded. Each pellet was again resuspended with approximately 7 ml of buffer. The entire material was combined in a 100 ml polypropylene container and stirred with a magnetic stirrer. The tubes were rinsed with small amounts of buffer, and the rinse water was added to the membrane preparation. The homogenized membranes were aliquoted into 1.5 ml microtubes and frozen at -70°C. Three aliquots were subjected to protein determination by FPB (fluorescamine protein binding) analysis. This procedure usually results in protein concentrations varying from 1-5 mg/ml.

Radioreceptor assay methods:

Each guinea pig lung preparation provided enough protein to last several months of analysis. Because of this, each preparation was analyzed for its 3H-LTD4 dissociation constant, number of receptor populations, number of binding sites per unit protein, and dose-response displacement characteristics of LTD4 and receptor antagonist FPL 55712.

Unless otherwise indicated, all binding experiments were performed in a final incubation volume of 250 µl. Tritiated LTD4 was obtained from New England Nuclear and non-radioactive LTD4 was obtained from Blomol Research Laboratories, Inc.

(Philadelphia, PA). Both substances were received in solution. 3H-LTD4 was dissolved in 509é EtOH with 0.01 M pH 6.8 phosphate buffer, while Biomol LTD4 was prepared in 6556 MeOH with 35% water and small amounts of AcOH and NH4OH. Both solutions were brought to appropriate analysis concentrations, by dilution in analysis buffer consisting of 50 mM Trisma 7.4 with 5 mM L-cysteine and 20 mM CaCl2. Membranes were also diluted with this analysis buffer. The compounds, except LTD4, were dissolved in DMSO and added to each tube in 5 µl aliquots. Diluent was added to all other appropriate control tubes. The incubations were carried out for 30 minutes at 25°C in a shaking water bath. Termination of the reaction was achieved by pouring the incubation solution over 2.5 cm Whatman GF/C filters soaked in assay buffer and placed over the openings of

Millipor filter vacuum manifolds. The filters were rinsed with 4 ml of ice-cold assay buffer three times. The filters were then removed, placed in 10 ml of Aquasol scintillation cocktail and then cooled in the dark for 2 h before counting. All samples were corrected for background and isotopic decay before converting the DPM determinations to the mass.

Determination of IC5Q values: LTD4 specific binding was determined as the difference between 3H-LTD4 binding alone and in the presence of 1 mM unlabeled LTD4. Nonspecific LTD4 binding was also removed from the tubes that also contained compound. Percent inhibition of binding for each dose of compound was calculated by subtracting specific binding in the presence of a compound from LTD4-specific binding in the absence of compound. This result was then divided by the unbound specific binding and multiplied by 100. These values were logit-transformed and linear regression was performed on the dose-response data. All dose-response plots used to calculate the ICsg values contained data from 3-6 compound concentrations Correlation coefficients for the linear model are always greater than 0.98 IC50 values were calculated from the regression equation for the line.

The compounds produced according to the present invention are formulated in pharmaceutically acceptable dosage forms using conventional means for those skilled in the art. The compounds may be administered in a number of dosage forms, e.g., such as oral dosage forms such as tablets, capsules, pills, powders or suppositories. They can also be administered intravenously, intraperitoneally, subcutaneously or intramuscularly using known pharmaceutical forms.

An effective but non-toxic amount of the compound is used in treatment. The dosage regimen for inhibition of LTB4 by the compounds of this invention is selected according to a number of factors including the type, age, weight, sex, and medical condition of the mammal, the particular disease and severity thereof, the route of administration, and the particular compound being used. used. A physician or veterinarian can readily determine and prescribe the effective amount of the compound to prevent or stop the worsening of the condition. In these cases, the doctor or veterinarian should use or use relatively low dosages at the beginning, and then increase the dosage until a maximum response is achieved. A dosage range of 1 to 25 mg/kg generally provides a therapeutically effective anti-inflammatory response.

The following examples illustrate the preparation of the compounds in the present invention from known starting materials. All temperatures are in °C unless otherwise stated.

US 4,665,203 filed on May 12, 1987, describes the methods for the production of some of the intermediate products that are used for the production of the compounds in the present invention.

Example 1

7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid.

(a) 493 mg of methyl 7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy-propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylate was added to 25 ml of acetone containing 276 mg of anhydrous potassium carbonate and 282 mg of methyl iodide. The mixture was refluxed for about 24 hours and water was added and the mixture was then extracted with ethyl acetate. The extract was dried, the solvent was removed under vacuum and the residual oil was chromatographed over silica gel with a 40/60 mixture of ethyl acetate/hexane to provide pure methyl ether, methyl 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-3,4-dihydro-8-propyl-2H- 1-benzopyran-2-carboxylate with the following formula

(b) Methyl ether (1a) (340 mg) was dissolved in methanol (5 mL) containing lithium hydroxide (0.7 mL of a 2N LiOH solution in water). The mixture was stirred at room temperature overnight, and the solvent was removed under vacuum. The residue was partitioned between ethyl acetate and 2N HCl and the organic layer was separated and washed with brine. Evaporation of the volatiles under vacuum afforded crude acid of formula III. This substance was purified by silica gel chromatography using ethyl acetate/hexane/acetic acid (40:60:0.5) as eluent. The pure product was recrystallized from ethyl acetate/hexane to provide 200 mg of product, 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-3,4-dihydro-8-propyl-2H-1 -benzopyran-2-carboxylic acid m.p. 65-68<>C.

Microanalysis: Found C 69.22, E 7.53

Theory C 69.40, H 7.49

NMR (CDCl 3 ) shows a -OHCH 3 at S 3.75.

Example 2

Comparative Test Data for Compound III

-OHCH3 compound (III) is thus approximately 5x more effective than the -OH compound in LTI^ receptor binding and at least 10x less active as an L/IT^ antagonist in the guinea pig intestinal muscle contraction test. The compounds of this invention are selective LTB 2 antagonists useful in the treatment of inflammatory disease. Example 3 7-[3-[4-acetyl-2-(cyclopropylmethyl)-3-methoxy enoxy]-propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid. (a) A mixture of zinc/copper couple (509 mg, 7.8 mmol), iodine (2 mg) and methylene chloride (2.09 g, 7.8 mmol) was heated at reflux for 30 min. The heat was removed and 2,4-dihydroxy-3-allylacetophenone (500 mg, 2.6 mmol) was added as a solution in ether. The mixture was heated at reflux for 2 hours and 2 g of methyl iodide was further added during this time. The mixture was cooled and stirred at room temperature for 10 hours. The mixture was filtered and the ether solution was washed sequentially with aqueous ammonium chloride, sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and evaporated under vacuum to provide a crude residue which was purified by column chromatography on silica gel (eluting with 2:8 ethyl acetate/hexane to provide 220 mg of 2,4-dihydroxy-3-cyclopropylmethylacetophenone. NMR < 1>H (S,CDC13) 0.25-0.5 (4H, m, cyclopropyl H's), 1.0 (1H, m, cyclopropyl H), 2.5 (3H, s, acetyl CH3, 2.65 (2H,d,CH2-ø) 6,4(1H,d,ArH), 7,5(lH,d,ArH) (b) 1,3 chlorobromopropane (1.9 g), methyl 7-hydroxy-8 -propyl chromane-2-carboxylate (2.5 g) and potassium carbonate (2.1 g) were stirred at RT 1 dry dlmethylformamld under argon 1 24 h. The mixture was poured into water and thoroughly extracted with ethyl acetate. The combined organic the extracts were sequentially washed with water and brine and then dried over magnesium sulfate Filtration and evaporation of the volatiles under vacuum provided 4.3 g of crude product which was chromatographed on silica gel (10:90 ethyl acetate/hexane) to provide 3.0 g methyl 7- (3-Chloropropoxy)-8-propylchroman-2-carboxylate. NMR-^-H (S, CDCl3), 0.8(3H,t.propyl CH3) 1.5-2.6 (8H,m propyl CH2's and ring CH2's), 3.7 (3H,s,CO2CH3) , 3.75 (2H,t,CH2Cl), 4.2 (2H,t,CH2OAc), 4.75(1H,d,CH-0Ar) 6.4 (1H,d,ArH), 6.8 ( lH,d,ArH) (c) 2,4-dihydroxy-3-cyclopropylmethylacetophenone (0.2 g), methyl 7-(3-chloropropoxy)-8-propylchroman-2-carboxylate (327 mg), sodium iodide (0, 15 g) and potassium carbonate (0.14 g) were stirred in 3 ml of dry dlmethylformamide (DMF) overnight at 45° under argon. The mixture was poured into water and thoroughly extracted with ethyl acetate. The combined organic extracts were washed with water and dried over magnesium sulfate. Evaporation of the volatiles under vacuum provided a crude oil which was purified by chromatography on silicon on silica gel to provide 98 mg of methyl 7-[3-[4-acetyl-2-(cyclopropylmethyl)-3-hydroxyphenoxy]propoxy]-3 ,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylate.

NMR: 1E(S, CBCl3) 0.2-0.45 (4E, m, cyclopropyl H's),

0.9 (3H, t,propyl CH3), 1.0(1H, m, cyclopropyl H), 1.4-2.8(12H, m, aliphatic and cyclic CH2's), 2.55 (3H, s, CH3CO), 3.75 (3H, s, CO2CH3), 4.25 (2H, t, CH2OAr), 4.35(2H,t, CH2OAr), 4.75(1H,m, CH-OAr),

6.4-7.6(4H,m,ArH's)

(d) Compound 3c (95 mg) was dissolved in acetone (5 mL) containing dimethyl sulfate (38 mg) and potassium hydroxide (12.4 mg) and the mixture was heated at 56°C under argon for 10 h. The solvent was removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with potassium carbonate solution and dried over magnesium sulfate. Evaporation of the volatiles under vacuum afforded a crude oil which was purified by chromatography on silica gel (1:9 ethyl acetate/hexane) for to provide 40 mg of pure methyl 7-[3-[4-acetyl-2-(cyclopropyl-

methyl )-3-methoxyphenoxy]propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylate.

NMR <i>HU.CDCl 3 ) 3.5(3H,s,OCH 3 ).

(e) Compound 3d (38 mg) was dissolved in 10.3 mL of methanol containing 74 µl of a 1M lithium hydroxide solution, and the solution was stirred overnight at room temperature. The solvent was removed and the residue was partitioned between ethyl acetate and 1056 hydrochloric acid solution. The organic layer was removed and dried over magnesium sulfate. Evaporation of the volatiles under vacuum afforded 35 mg of the title compound,

7-[3-[4-acetyl-2-(cyclopropylmethyl)-3-methoxy enoxy]-propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid.

Microanalysis: Found C 69.51, H 7.34

Calculated for C29H36O7.1/4H20: C 69.30,

Example 4

7-[[3-(4-acetyl-3-methoxy-2-propylphenoxy)cyclopentyl]oxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid.

(a) 2,4-dihydroxy-3-propyl-3-propylacetophenone (1.94 g), 1,3-dihydroxycyclopentane (1.02 g), triphenylphosphine (2.62 g) and diethyl azodicarboxylate (1.7 g) was dissolved in dry tetrahydrofuran (THF) (200 mL) and stirred under argon at room temperature overnight. The solvent was evaporated and the crude residue was purified by silica gel chromatography (Merck 60, 4:6 ethyl acetate/hexane) to provide 1.5 g of 1-(2-propyl-3-hydroxy-4-acetylphenoxy)-3-hydroxycyclopentane.

NMR 1-H (5, CDCl 3 ) 0.9 (3H,t,propyl CH 3 ),

1.3-2.6(10H, aliphatic and cyclic CH2's), 2.55 (3H,s,CE3CO), 4.4 (1H, m, CH-0H), 4.9 (1E, m, CH- 0Ar), 6.4 (1E, d, ArE), 7.6 (1E, d, ArH)

(b) Compound 4a (1.4 mg, 5.0 mmol), methyl 7-hydroxy-8-propylchroman-2-carboxylate (1.33 mg, 5.01 mmol), triphenylphosphine (1.32 mg, 5, 0 mmol) and diethyl azodicarboxylate (875 mg) were dissolved in dry tetrahydrofuran (120 mL) and stirred under argon at room temperature for 10 hours. The solvent was evaporated and the solid residue was dissolved in dry ether and filtered through sintered glass. The filtrate was evaporated and the residue was purified by chromatography on silica gel using 2:8 ethyl acetate/hexane as eluent. 0.7 g of methyl 7-[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)cyclopentyl]oxy]-3,4-dihydro-8-propyl-2E-1-benzopyran-2-carboxylate was delivered .

NMR ^(S, CDCl3) 0.9(6H,t, propyl CH3's), 1.5-2.7 (18H, aliphatic and cyclic CH2's), 2.55(3E,s,CE3CO),

3.75 (3E,s, 0CE3), 4.75(1H,m,CE-C02CH3),

4.9(1H,m,CH-0Ar), 5.0(1H,m,CH-0Ar), 6.4 (2E,2ds,ArE's)

6.8(lH,d,ArH), 7.55(lH,d,ArH) (c) Compound 4b (419 mg, 0.8 mmol) was dissolved in acetone (10 mL) containing potassium hydroxide (55.3 mg , 0.98 mmol), and dimethyl sulfate (134.5 mg). The mixture was heated at 45°C for two hours and then cooled, and the volatiles were removed under vacuum. The residue was partitioned between ethyl acetate and water and the organic layer was separated" and dried over magnesium sulfate. Removal of the solvent provided a crude oil which was purified using radial band chromatography (Harrison chromatotron, 2:8 ethyl acetate/hexane as eluent). Methyl 7 -[[3-(4-acetyl-3-methoxy-2-propylphenoxy)-cyclopentyl]oxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylate was provided as pure colorless oil ( 270 mg).

NMR <1>H(S,CDCl3) 0.9(6H, 2t's, propyl CH3's),

1.5-2.8 (18H, aliphatic and cyclic CH2<*>s), 2.6 (3H, s, CH3CO), 3.75 (3H, s, 0CH3 ether), 3.77 (3H,s ,0CH3 ester), 4.75 (1H,m, CHC02CH3), 4.9 (1H,m, CH-OAr), 5.0 (1H,m CH-0Ar), 6.4(1H,d, ArH ), 6.65 (lH,d, ArH),

6.8(lH,d,ArH), 7.55 (lH.d.ArH)

(d) Compound 4c (150 mg) was dissolved in methanol (2 mL) containing 1M lithium hydroxide (450 µL) and the mixture was stirred at room temperature overnight. The volatile substances were removed under vacuum and the residue was partitioned between ethyl acetate and dilute hydrochloric acid. The organic layer was separated and dried over magnesium sulfate. Removal of solvent provided the title compound,

7-[[3-(4-acetyl-3-methoxy-2-propylphenoxy)cyclopentyl]oxy]-3,4-dihydro-3-propyl-2H-1-benzopyran-2-carboxylic acid.

NMMR ^(S, CDCl 3 ) no 0CH 3 ester at 3.77.

Example 5

7-[3-[4-acetyl-3-methoxy-2-(2-propenyl)phenoxy]propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid.

(a) 2,4-dihydroxy-3-(2-propenyl) acetophenone (Aldrich, 12.5 g, 65 mMol) and methyl 7-(3-iodopropoxy)-8-propyl-chroman-2-carboxylate (29, 9 g, 71.5 mmol) was dissolved in DMF (300 mL) containing powdered potassium carbonate (26.91 g, 195 mmol). The mixture was stirred at room temperature under nitrogen for 8 hours and then partitioned between water and toluene. The organic layer was separated and washed with water and brine and then dried over sodium sulfate. Evaporation of the volatiles under vacuum afforded 36 g of a crude product which was chromatographed on Merck 60 silica gel using 5:95 ethyl acetate/toluene as eluent. 25 g of pure methyl 7-[3-[4-acetyl-3-hydroxy-2-(2-propenyl)phenoxy]propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylate was provided in this way.

NMR % (5, CDCl3) 0.9(3H,t,propyl CH3), 1.4-2.8(0H, aliphatic and cyclic CH2's), 2.55 (3H,d, CH3CO),

3.45(2H,d,ArCH2CH=CH2), 3.75 (3H,s,CO2CH3),

4.09(2H,t, CH2OAr), 4 .22(2H,t,CH2OAr)

4.75(1H,t,CHOAr), 4.85-5.00(2H,m,allyl H's),

5.75-6.1(1H,m,allyl CH) 6.4-7.12(4H,ArH's )

(b) Compound 5a (20.6 g, 42.7 mmol) was dissolved in dry DMF (105 mL) containing methyl iodide (18.4 g, 128.5 mmol) and powdered potassium carbonate (17.69 g, 128 mmol) ). The mixture was stirred under nitrogen at room temperature for 22 hours and then partitioned between water and toluene. The organic layer was separated, washed with water and brine and dried over sodium sulfate. Removal of volatiles under vacuum afforded 21 g of product which was methyl 7-[3-[4-acetyl-3-methoxy-2-(2-propenyl)phenoxy]-propoxy]-3,4-dihydro-8-propyl -2H-1-benzopyran-2-carboxylate.

NMR 1H(S, CDCl 3 ) 3.77 (3H, s, 0CH 3 ether)

(c) Compound 5b (16.96 g, 34.15 mmol) was dissolved in methanol and a lithium hydroxide solution in water (4.3 g in 43 mL 102.5 mmol) was added. The mixture was stirred at room temperature for 3 hours and the solvent was removed under vacuum. The mixture was partitioned between toluene and dilute hydrochloric acid and the organic layer was removed. The organic extract was washed sequentially with water, brine and then dried over sodium sulfate. Evaporation of the volatiles under vacuum afforded a yellow oil which was purified by silica gel chromatography on Biosil A using 20% ethyl acetate in toluene as eluent. The product, 7-[3-[4-acetyl-3-methoxy-2-(2-propenyl)-phenoxy]propoxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid was isolated as a light yellow oil, 15 g, which was recrystallized from ethyl acetate/hexane, m.p. 85.5°C.

Microanalysis: Found, C 69 .69 , H 7.10.

Calculated for C28<B>35°7. C 69.6, H 6.98.

Example 6

7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid

(a) 2,4-dihydroxyacetophenone (7.1 g, 0.05 mol) and dimethyl oxylate (7.2 g) were dissolved in DMF containing a sodium methoxide in methanol solution (4.0 g Na, 100 mL MeOH) and the mixture was stirred at room temperature for 48 h. Then acetic acid (180 ml) was added and the mixture was heated to 100°C for 5 hours. The solvent was removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was thoroughly extracted with more ethyl acetate, and the combined

the organic extracts were washed with saline. Evaporation of dried (Na 2 SO 4 ) solvent in vacuo afforded methyl 7-hydroxy-4-oxo-4H-1-benzopyran-2-carboxylate (6a) as a crude yellow solid which was crystallized from ethyl acetate/hexane to afford 3, 5 g of pure product.

NMR XE (S, CDCl 3 ) 4.0 (3H, s, CO 2 CH 3 ), 6.85

(1H, s, chromenone H) 6.9 - 8.0 (3H, Ar H's)

(b) Compound 6a (3.57 g, 16 mmol) was dissolved in ethyl acetate containing phosphoric acid and 5% palladium on carbon. The mixture was shaken in a Parr apparatus at room temperature under a hydrogen atmosphere for 22 hours. The solution was filtered and washed with water, and the organic layer was dried over magnesium sulfate. Evaporation of the volatiles under vacuum afforded a crude oil which was purified by silica gel chromatography using ethyl acetate/hexane 6:4 as eluent. 3.3 g of the product, methyl 7-hydroxychroman-2-carboxylate, (6b) was provided as a clear oil.

NMR: ^ (S, CDCl3) 2.1-2.8 (4H, m, cyclic CH2's 3.8(3H,s, CO2CH3), 4.7 (1H, dd, CHOAr), 6.35-6, 9(3H, Ar H's) (c) Compound 6b (416 mg, 2 mmol) and 3-(2-propyl-3-hydroxy-4-acetylphenoxy)-1-iodopropane (720 mg, 2 mmol) were dissolved in dry DMF (3 mL) containing powdered anhydrous potassium carbonate (552 mg, 4 mmol) and the mixture was stirred at 60 °C for 10 h. The mixture was cooled and partitioned between ethyl acetate and water. The organic layer was separated, washed with water and dried over magnesium sulfate. Evaporation of the volatiles under vacuum afforded a crude oil which was purified by flame corona radiography on Merck 60 silica gel using ethyl acetate and hexane (2.5:7.5) as eluent. 540 mg of the product, methyl 7-[3 -(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylate, (6c) was provided.

NMR %($, CDCl 3 ) 0.9 (3H, t, propyl H's),

1.4-2.8 (10H, cyclic CE2's and aliphatic CE2's), 2.55(3E,s,CE3C0) 3.79 (3E,s,0CE3), 4.2 (2E,t~,0Ar), 4.2 (2H,t,0Ar), 4.7 (1E,m,CE-OAr) 6.4-7.6(5H,ArE's )

(d) Compound 6c (250 mg) was dissolved in distilled acetone (5 mL) containing potassium hydroxide (41.8 mg) and dimethyl sulfate (117.6 mg). The mixture was heated with stirring under argon at 40° C. for 10 hours. The mixture was cooled, the solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was separated and dried over magnesium sulfate. Evaporation of the volatiles under vacuum afforded 240 mg of the product, methyl 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy]-3,4-dihydro-8-propyl-2E-1- benzopyran-2-carboxylate, (6d) which was homogeneous by TLC. NMR %($, CDCl 3 ) 3.65 (3H, s, 0CH 3 ) (e) Compound 6d (200 mg) was dissolved in methanol (3 mL) containing lithium hydroxide (1.0 mL of a 1 M solution) and the mixture was stirred at room temperature for 10 hours. The solvent was removed and the residue was partitioned between ethyl acetate and dilute hydrochloric acid. The organic layer was separated, washed with brine and dried over sodium sulfate. Evaporation of the volatiles under vacuum provided 40 mg of the product, 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid, which a rubber.

Microanalysis: Found C 67.59, H 6.93.

Calculated for C25<H>30<O>7, C 67.86, H 6.83.

Example 7

7 - [3 - (4 - Acetyl-3-methoxy-2-propylphenoxy)propoxy]-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid.

(a) Methyl 7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propoxy]-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate (250

mg, 0.48 mmol) was dissolved in 1 acetone (10 mL) containing potassium hydroxide (35 mg, 0.53 mmol) and dimethyl sulfate (78.3 mg 0.62 mmol). The mixture was heated at reflux temperature for 10 hours and then cooled. The residue was partitioned between ethyl acetate and water and the organic layer was separated and dried over sodium sulfate. The solvent was removed under vacuum to provide 260 mg of the product, methyl 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-4-oxo-8-propyl-4H-1-benzopyran-2 -carboxylate.

NMR: %(§, CDCl 3 ) 0.9 (6H, 2t's, propyl CH 3 's).

1.4-2.8 (10H, aliphatic CH2's), 3.75(3H,s,0CH3 ether). 4.0(3H,s,CH3 ester), 4.25(2H,t,CH20Ar ), 4.35

(2H,t,CH2OAr) 7.05 (1H,s, olefinic H) 6.7, 7.05, 7.55 and 8.05

(4H, d's, Ar H's)

(b) Compound 7a (200 mg, 0.4 mmol) was dissolved in methanol (2 mL) containing 0.48 mL of a 1M lithium hydroxide solution. The mixture was stirred at room temperature for 10 hours and the solvent was removed. The residue was partitioned between ethyl acetate and dilute hydrochloric acid and the organic layer was separated, dried over magnesium sulfate, filtered and evaporated under vacuum. The product, 7-[3-(4-acetyl-3-methoxy-2-propyl-phenoxy)-propoxy]-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid, was isolated as a light yellow gum (122 mg, 62% yield).

Microanalysis: Found C 66.43, H 6.59. Calculated for C28H32108.l/2 H20; C 66.43, H 6.59.

Example 8

7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy]-3,4-dihydro-N-methyl-8-propyl-2H-1-benzopyran-2-carboxamide.

The compound of Example 1 (80 mg) was treated with a small excess of oxalyl chloride and the mixture was allowed to stand at room temperature for 2 hours. The mixture was stripped, dissolved in methylene chloride, and methylamine gas was bubbled into the reaction mixture. The mixture was washed with water, dried over magnesium sulfate, filtered and the solvent was evaporated under vacuum. The resulting white solid was washed with ethyl acetate/hexane (2:8) and dried under vacuum. 60 mg of the product was provided.

Microanalysis: Found C 69.63, H 7.96, N 2.86,

Calculated for C29<H>3gNO6, C 70.00, H 7.9, N 2.82.

Example 9

Methyl 7-[[5-(4-acetyl-3-methoxy-2-propylphenoxy)pentyl]oxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylate.

Methyl 7-[[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyl]-oxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylate (ImMol), prepared as described in US 4,565,882, 1 acetone containing 2.5 equivalents of potassium hydroxide and 3 equivalents of dimethyl sulfate was dissolved. The mixture was heated at 40°C for 10 hours and then cooled; the solvent was removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was separated and dried over magnesium sulfate. Evaporation of the volatile substances under vacuum provided methyl ether.

NMR ^(S.CDCls)

0.9 (6H, 2t's, propyl CH3's), 1.4-2.8(18H, aliphatic and cyclic CH2's), 2.55 (3H,s, CE3CO), 3.75 (3H, s, 0CH3) 3 .85 (3H, s, 0CH3), 3.9 (2H, t, CH2OAr), 4.1

(2H, t, CH2OAr), 4.7 (1H, dd CHOAr), 6.4, 6.65, 6.8 and 7.55 (4H, ArH's)

The compounds of Examples 10 to 14 were prepared according to the procedure described in Example 9 starting with the appropriate phenol.

Example 10

Methyl 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-3,4-dihydro-2-methyl-4-oxo-8-propyl-2H-1-benzopyran-2-propanoate.

The title compound was prepared according to the procedure in Example 9 from methyl 7-[3(4-acetyl-3-hydroxy-2-propyl-phenoxy)propoxy]-3,4-dihydro-2-methyl-4-oxo-8 -propyl-2H-1-benzopyran-2-propanoate, which was prepared as described in US 4,665,203.

NMR ^(S.CDCls)

0.9(6H, 2ts, propyl CH3's), 1.4-2.7 (16H, aliphatic and cyclic CH2's), 1.35 (3H,s,CH3), 2.6(3H, s, CH3CO),

3.7(3H, s, 0CH3), 3.75 (3H,s, 0CH3), 4.25 (4E,

CH2OAr), 6.6, 6.7, 7.6 and 7.75 (4H, d's, ArH's)

Example 11

Methyl 7-[[4-(4-acetyl-3-methoxy-2-propylphenoxy)-2-butyn-yl]oxy]-3, 4-dihydro-2-methyl-4-oxo-8-propyl-2H- 1-benzopyran-2-propanoate.

The title compound was prepared by the method of Example 9 from methyl 7-[[4-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-2-butynyl]oxy]-3,4-dihydro-2-methyl-4 -oxo-8-propyl-2H-1-benzopyran-2-propanoate.

NMR ^(S.CDCls)

0.9 (6H, 2t's, propyl CH3<*>s), 1.4-2.7 (14H, aliphatic and cyclic CH2's), 1.35 (3H, s, CH3), 2.6 (3H, s , CH3CO), 3.7 (3H, s, 0CH3), 3.75 (3H, s, 0CH3), 4.8 (4H, s, CH2OAr) 6.6, 6.7, 7.65 and 7, 75 (4H, d's, ArH's)

Example 12

Methyl 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-1,2,3,4-tetrahydro-8-propyl-2-naphthalenecarboxylate.

(a) 1.6 g of 3-(2-n-propyl-3-hydroxy-4-acetylphenoxy)-1-bromopropane (.005 mol) which was prepared as described in US Patent 4,565,882 (Miyano et al. ) was dissolved in 30 ml of methyl ethyl ketone. Two grams (2.5 equivalents) of potassium carbonate were added to the reaction along with 1.25 g (.005 mol) of methyl

1,2,3,4-tetrahydro-7-hydroxy-8-propyl-2-naphthalene carboxylate provided in Example 28. After 100 mg of sodium iodide was added, a nitrogen blanket was placed on the system and the contents were refluxed for 48 hours. The reaction was cooled to room temperature. The mixture was filtered and the filtrate evaporated. The residue was chromatographed on silica gel eluting with 356 acetone toluene. Evaporation of the eluent provided 1.45 g (6056) of compound (12a), methyl 7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-1,2,3,4-tetrahydro -8-propyl-2-naphthalenecarboxylate, sm. at 84-85°C.

Microanalysis: Calculated: C, 72.17; H, 7.94; for C2gH380(,

Found: C, 71.87; H, 7.90.

(b) The title compound was prepared by the method of Example 9 from methyl 7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-1,2,3,4-tetrahydro-8-propyl- 2-Naphthalene Carboxylate.

NMR ^(S.CDC^)

0.95(6H, 2t's, propyl CH3's), 1.4-3.1 (16H, aliphatic and cyclic CH2's), 2.6 (3H, s, CH3C0), 3.75 (6H, 2 overlapping units, 0CH3's ), 4.5 (2H, t, CH2OAr), 4.25 (2H, t, CH2OAr), 6.7, 6.9, 7.55 (4H, Ar H's)

Example 13

Methyl 3,4-dihydro-7-[3-[3-methoxy-4-(2-methyl-1-oxopropyl)-2-propylphenoxy]propoxy]-8-propyl-2H-1-benzopyran-2-carboxylate.

(a) A solution of 495 mg (1.89 mmol) triphenylphosphine, 420

mg (1.89 mmol) of 2,4-dihydroxy-3-propylisobutyrophenone, 582 mg (1.89 mmol) of methyl 7-(3-hydroxypropoxy)-8-n-propylchroman-2-carboxylate in 5 ml of tetrafuran were prepared and cooled in an ice bath. Diethylazocarboxylate, 350 mg (1.89 mmol) was added and the solution was warmed to room temperature and stirred for 18 hours.

The solvent was removed by rotary evaporation and the residue was triturated with 25 ml of ether, cooled and filtered. The ether filtrate was then washed with water, brine, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and ether was removed by rotary evaporation, and the residue was purified by elution chromatography on silica gel with 156 acetonetoluene to provide 720 mg (7556) of the desired ester, methyl 3,4-dihydro-7-[3- [3-Hydroxy-4-(2-methyl-1-oxopropyl)-2-propyl-phenoxy]-propoxy-8-propyl-2H-1-benzopyran-2-carboxylate, as an oil.

Microanalysis: Calculated: C, 70.08; H, 7.86;

Found: C, 69.51; H, 7.81. (b) The title compound was prepared by the method of Example 9 from methyl 3,4-dihydro-7-[3-[3-hydroxy-4-(2-methyl-1-oxypropyl)-2-propylphenoxy]-propoxy]-8 -propyl-2H-1-benzopyran-2-carboxylate.

NMR ^(S.CDCls)

0.9(6H, 2t's, propyl CH3's), 1.15 (6H, d, (CH3)2CC0), 1.4-2.7 (14H, aliphatic and cyclic CH2's), 3.7 (3H,s, OCH3) 3.75 (3H, s, OCH3), 4.15, 4.2 (4H, 2fs, CH20Ar), 4.75 (1H, Idd, CHOAr), 6.4, 6.7, 6.8 and 7.35 (4H, d's, ArH's)

Example 14

Ethyl 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-propanoate. The title compound was prepared by the method of Example 9 from ethyl 7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran- 2-propanoate which was prepared as described in US 4,665,203.

NMR ^(S.CDCls)

0.9 (6H, 2ts, propyl CH3's), 1.2-2.7 (20H, aliphatic cyclic and C02CH2CH3 H's), 2.6 (3H, s, CH3CO),

3.75 (3H, s, 0CH3), 4.0 (1H, m, CHOAr), 4.1, 4.3 (4E, 2 triplets, CB20Ar), 6.4, 6.7, 6.8 7 .55 (4H, ArH's)

Example 15

7-[[5-(4-acetyl-3-methoxy-2-propylphenoxy)pentyl]oxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid.

The compound prepared in Example 9 (1 mmol) was dissolved in methanol containing two equivalents of a 1M lithium hydroxide solution in water. The mixture was stirred at room temperature for 10 hours and then the solvent was removed under vacuum. The residue was partitioned between ethyl acetate and water, and the organic layer was separated and dried over magnesium sulfate and the volatiles were removed under vacuum. The product carboxylic acid can be purified by column chromatography on silica gel if necessary.

NMR 1-BXS.CDCls) 0.9(6B, 2ts, propyl CH3's),

1.4-2.8 (18H, aliphatic and cyclic CH2's), 2.55 (3H, s, CH3CO), 3.75(3H, s, OCH3), 3.9(2H, t, CH2OAr), 4 .1 (2H, t, CH2OAr) 4.75(1H, m, CHOAr), 6.4, 6.65, 6.8 and 7.55 (4H, ArH's)

Example 16

7 - [ 3 - ( 4 -acety 1 -3-me toc sy-2-propyl phenoxy) propoxy] -3 , 4-dihydro-2-methyl-4-oxo-8-propyl-2H-1- benzopyran-2-propanoic acid.

The title compound was prepared from the compound of Example 10 using the procedure of Example 15.

Microanalysis: Found: C 68.55, H 7.60.

Calculated for C31<H>40<0>8<:> C 68.87, H 7.46.

Example 17

7-[[4-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-2-butynyl]oxy]-3,4-dihydro-2-methyl-4-oxo-S-propyl^H-1-benzopyran ^-pro<p>ans<y>re .

The title compound was prepared from the compound of Example 11 using the procedure of Example 15.

NMR <i>H (α, CDCl3) 0.9 (6H, 2t's, propyl CH3's),

1.4-2.7 (14H, aliphatic and cyclic CH2's), 1.35 (3H, s, CH3), 2.6 (3H, s, CH3CO), 3.75 (3H, s, 0CH3), 4 .85 (4E, brs, CH2OAr), 6.6, 6.7, 7.6 and 7.75 (4H, d's, ArH's)

Example 18

7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-1,2,3,4-tetrahydro-8-propyl-2-naphthalenecarboxylic acid.

The title compound was prepared from the compound of Example 12 using the procedure of Example 15.

Microanalysis: Found: C 71.85, H 7.94.

Calculated for C24<H>3<g0>6: C 72.17, H 7.94.

Example 19

3,4-dihydro-7-[3-[3-methoxy-4-(2-methyl-1-oxopropyl)-2-propylphenoxy)propoxy]-8-propyl-2H-1-benzopyran-2-carboxylic acid.

The title compound was prepared from the compound of Example 13 using the procedure of Example 15.

NMR ^(S, CDCl3) 0.9 (6H, 2t's, propyl CH3's), 1.15

(6H, d, (CH3)2CC0), 1.4-2.7 (14H, aliphatic and cyclic CH2's), 3.7 (3H, s, 0CH3), 4.15, 4.2 (4H, 2t's,

CH20Ar) 4.75 (1H, dd, CEOAr), 6.4, 6.7, 6.82 and 7.35

(4H, d's, ArH's)

Example 20

7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-propanoic acid.

The title compound was prepared from the compound of Example 14 using the procedure of Example 15.

NMR <*>H (5, CDCl3) 0.9 (6H, 2ts, propyl CH3's)

1.2-2.7 (18H, aliphatic and cyclic CH2's), 2.6 (3H, s, CH3CO) 3.75 (3H, s, OCH3), 4.0 (1H, m, CHOAr), 4, 1

4.3 (4H, 2t's, CH2OAr), 6.4, 6.7, 6.8, 7.55 (4H, ArH's)

Example 21

7-[3-(4-acetyl-3-ethoxy-2-propylphenoxy)-propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid.

(a) 4-(3-chloropropoxy)-2-hydroxy-3-propylacetophenone (5.0 g, 18.4 mmol), potassium carbonate (7.3 g) and iodoethane (3.0 mL) were dissolved in 1 dry DMF (50 mL) and the mixture was stirred overnight at room temperature. The reaction mixture was then partitioned between ether and water and the organic layer was separated. The ether extract was washed with water and saline, and then dried over sodium sulfate. Evaporation of the volatiles under vacuum afforded 5.36 g of crude 4-(3-chloropropoxy)-2-ethoxy-3-propylacetophenone.

(b) 4-(3-chloropropoxy)-2-ethoxy-3-propylacetophenone (5.36 g) was dissolved in acetone containing 10 equivalents of sodium iodide, and the mixture was refluxed under nitrogen for 10

hours. Solvent was removed under vacuum and the residue was partitioned between ether and water. The organic extracts were washed with water and brine, dried over sodium sulfate and evaporated in vacuo to provide 7.0 g of yellow oil, 4-(3-iodopropoxy)-2-ethoxy-3-propyl-acetophenone.

NMR <i>H (S, CDCl 3 ) 300 MH 2 3.4 (2H, t, CH 2 I).

(c) Compound 21b (2.34 g, 6 mmol), methyl 7-hydroxy-8-propylchroman-2-carboxylate (1.25 g, 5 mmol) and potassium carbonate (2.07 g, 15 mmol) were suspended in dry DMF (12.5 mL) and the mixture was stirred at room temperature for 48 h. The mixture was then partitioned between ether and water and the ether layer was separated, washed with water and brine, and then dried over sodium sulfate. Evaporation of the volatiles under vacuum provided 2.9 g of crude product, which was purified by chromatography on silica gel to provide 1.34 g of pure methyl 7-[3-(4-acetyl-3-ethoxy-2-propylphenoc- sy )propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylate. (d) Compound 21c (0.8 g, 1.56 mmol) was dissolved in methanol/water (7:3, 25 mL) containing lithium hydroxide (0.13 g, 3.12 mmol). The mixture was stirred at room temperature for 2 hours and then partitioned between dilute hydrochloric acid and ether. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated under vacuum to provide 1.1 g of crude product. This material was purified by chromatography on silica gel using ethyl acetate/hexane/acetic acid (50:50:1) as eluent. 7-[3-(4-acetyl-3-ethoxy-2-propyl-phenoxy)-propoxy]-3,4-dihydro-8-propyl-2E-1-benzopyran-2-carboxylic acid was provided as 0.71 g of white crystals m.p. 81-84<*>0.

Microanalysis: Found C 69.68, E 7.85.

Calculated for CsnH^Oy, C 69.85, E, 7.68.

Example 22

7 - [3 - (4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-4-oxo-8-propyl-4E-1-benzopyran-2-propanoic acid

Starting with methyl 7-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)propoxy]-4-oxo-8-propyl-4H-1-benzopyran-2-propanoate and then using the method in example 9 , provided 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-4-oxo-8-propyl-4H-1-benzopyran-2-propanoate which was hydrolyzed using the procedure of Example 15 for providing the title compound.

Microanalysis: Calculated: C, 68.62; H, 6.92.

Found: C, 68.24; H, 6.92.

Example 23

Methyl 7-[[4-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-butynyl]-oxy]-3,4-dihydro-2-methyl-4-oxo-8-propyl-2H-1 -benzopyran-2-propanoate

A solution of 2.04 g (7.8 mmol) of 4-(4-hydroxy-2-butynyloxy)-2-hydroxy-3-propylacetophenone, 2.49 g (7.8 mmol) of methyl -(3,4 -dihydro-7-hydroxy-2-methyl-4-oxo-8-propyl-2H-1-benzopyran-2-yl)propanoate, and 2.04 g (7.8 mmol) of triphenylphosphine were prepared in 50 ml of dry tetrahydrofuran . After addition of 1.22 ml (7.8 mmol) of diethyldiazodicarboxylate, the solution was stirred for 18 hours.

Tetrahydrofuran was removed by rotary evaporation and the residue was stirred in 50 ml of ether. Insoluble solids were removed by filtration and the ether filtrate was concentrated by rotary evaporation to provide 5.94 g of crude oil. The oil was purified by elution chromatography to provide 3.2 g (73%) of the methyl ester product. Microanalyse: Calculated: C, 70.19; H, 7.14.

Found: C, 70.33; H, 7.18.

Example 24

Trans-methyl 7-[[4-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-butenyl]oxy]-3, 4-dihydro-2-methyl-4-oxo-8-propyl-2H- 1-benzopyran-2-propanoate

A solution of 3.05 g (11.5 mmol) of trans-4-(4-hydroxy-2-butenyloxy)-2-hydroxy-3-propylacetophenone, 3.70 g (11.5 mmol of methyl 3-(3, 4-dihydro-7-hydroxy-2-methyl-4-oxo-8-propyl-2H-1-benzopyran-2-yl)propanoate, and 3.03 g (11.5 mmol) of triphenylphosphine in 75 mL of dry tetrahydrofuran was prepared.Diethyl diazodicarboxylate, 1.80 mL (11.5 mmol), was added and the solution was stirred for 18 hours at room temperature.

Solvent was removed from the reaction mixture by rotary evaporation and 75 ml of ether was added to the residue and stirred. After removal of insoluble solids by filtration, the ether filtrate was removed by rotary evaporation. The resulting crude was purified by silica gel eluting chromatography with 756 ethyl acetate toluene to provide 4.73 g (7356) of the methyl ester as an oil.

Microanalysis: Calculated C, 69.94; H, 7.47.

Found: C, 70.02; H, 7.45.

Example 25

Trans-7-[[4-(4-acetyl-3-methoxy-2-propylphenoxy)-2-buten-yl]oxy]-3,4-dihydro-2-methyl-4-oxo-8-propyl-2H -1-benzopyran-2-propanoic acid

The compound of Example 24 was methylated using the procedure of Example 9 to provide 7-[[4-(4-acetyl-3-methoxy-2-propylphenoxy)-2-butenyl]ok sy]-3,4-dihydro- 2-methyl-4-oxo-8-propyl-2H-1-benzopyran-2-propanoate which was then hydrolyzed using the procedure of Example 15 to provide the title compound.

Example 26

Cis-methyl 7-[[4-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-butenyl]oxy]-3, 4-dihydro-2-methyl-4-oxo-8-propyl-2H- 1-benzopyran-2-propanoate

A solution of 5.82 g (22 mmol) cis-4-(4-hydroxy-2-butenyloxy)-2-hydroxy-3-propylacetophenone, 7.05 g (22 mmol) methyl-(3,4-dihydro- 7-hydroxy-2-methyl-4-oxo-8-propyl-2H-1-benzopyran-2-yl)propanoate, and 5.77 g (22 mmol) of triphenylphosphine were prepared in 150 ml of dry tetrahydrofuran. After addition of 3.5 ml (22 mmol) of diethyl diazodicarboxylate, the mixture was stirred for 18 hours.

Tetrahydrofuran was removed by rotary evaporation and the residue was stirred with 100 ml of ether. Insoluble solids were removed by filtration and the ether filtrate was concentrated by rotary evaporation to provide 16.6 g of yellow oil. The oil was purified by silica gel chromatography using 1096 ethyl acetate-toluene to provide 6.28 g

(5056) of pure methyl ester product.

Microanalysis: Calcd.: C, 69.94; H, 7.47.

Found: C, 69.52; H, 7.36.

Example 27

Cis-7-[[4-(4-acetyl-3-metocy-2-propylphenoxy)-2-butenyl]-oxy]-3,4-dihydro-2-methyl-4-oxo-8- propyl-2H-1-benzopyran-2-propanoic acid

The compound of Example 26 is methylated using the procedure of Example 9 to provide 7-[[4-(4-acetyl-3-methoxy-2-propylphenoxy)-2-butenyl]-oxy]-3, 4-dihydro-2-methyl-4-oxo-8-propyl-2H-1-benzopyran-2-propanoate which was then hydrolyzed using the procedure of Example 15 to provide the title compound.

Example 28

7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-3,4-dihydro-4-hydroxy-8-propyl-2E-1-benzopyran-2-propanoic acid

Beginning with methyl 7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-4-hydroxy-8-propyl-2H-1-benzo-zopyran-2- propanoate which was prepared as described in US 4,665,203 and methylation of the compound using the method of Example 9 and then hydrolyzing the product according to the method of Example 15 provides the title compound.

Table 1 and table 2 show the test results for some preparations of the invention. Table 3 shows the LTD4 receptor binding assay results. The form shows a general method for producing the compounds according to the present invention.

y - 0 to 2

x = 2 to 5

B = CH2, C = 0, C-OH

R<2> = methyl or ethyl R<3> = alkyl

R<5> = H, alkyl or

r<5> and R<6> form a carbon to carbon bond

R<4> = H or alkyl

R<*> = alkyl, alkenyl or CH2-R, and

R = cyclopropyl

R<7> = alkyl

Claims (1)

1. Analogous process for the preparation of therapeutically active, alkoxy-substituted dihydrobenzopyran-2-carboxylate derivatives with formula: and pharmaceutically acceptable salts thereof in which R<*> stands for alkyl with 2-6 carbon atoms, alkenyl with 2 to 6 carbon atoms or CH2R in which R stands for cyclopropyl; R<2> stands for methyl or ethyl; R<3> stands for alkyl of 1 to 5 carbon atoms; W stands for (CH 2 ) X where x is 2 to 5, alkenyl of 3 to 5 carbon atoms, alkynyl of 3 to 5 carbon atoms, or cyclopentyl; R<4> stands for hydrogen, alkyl of 2 to 5 carbon atoms; B stands for CH2, C=0 or CH-OH; R<5> stands for hydrogen, alkyl with 1 to 4 carbon atoms, or R^ and R<6> together optionally stand for a carbon to carbon bond; and A stands for -Z-C02R<7> or -Z-CONR<9>R10 where R<7> stands for hydrogen or alkyl with 1 to 4 carbon atoms, R<9> and R<10 >stand for hydrogen, alkyl with 1 to 4 carbon atoms, and in which Z is a direct bond or an ethylene chain, characterized by alkylating a compound with the general formula: wherein Ri, R<3>, R4 R^, VJ, A and B have the same meanings as described above and, if desired, hydrolyze group A to provide the free acid which is optionally converted to the pharmaceutically acceptable salt.